Intestinal
nematode infection induces
pulmonary eosinophilia via
IL-33, although the mechanism of pulmonary
IL-33 induction remains unclear. Because nematode migration damages lungs, we speculated that lung-derived damage-associated molecular patterns (DAMPs) possess an IL-33-inducing activity (IL33ia). Indeed, intra-
nasal administration of a lung extract induced
IL-33 production in lungs. Additionally, lung extracts increased
Il33 mRNA expression in primary lung fibroblasts. Proteomic analysis identified
retinoblastoma-
binding protein 9 (RBBP9) as a major DAMP with IL33ia. RBBP9 was originally discovered as a
protein that provides cells with resistance to the growth inhibitory effect of
transforming growth factor (TGF)-β1. Here, we found that stimulation by RBBP9 induced primary fibroblasts to produce
prostaglandin E2 (
PGE2) that, in turn, induced fibroblasts to produce
IL-33. RBBP9-activated fibroblasts expressed mRNAs of
cyclooxygenase-2 (COX-2) and
PGE2 synthase-1 that convert
arachidonic acid to
PGE2. Furthermore, they expressed
PGE2 receptors E-
prostanoid (EP) 2 and EP4. Thus, treatment with a
COX-2 inhibitor or EP2 and/or EP4 receptor antagonists inhibited RBBP9-induced
IL-33 production.
Nematode infection induced pulmonary
Il33 mRNA expression, which was inhibited by the
COX-2 inhibitor or EP2 and EP4 antagonists, suggesting that
nematode infection induced pulmonary
Il33 mRNA via
PGE2. RBBP9 was expressed constitutively in the lung in the steady state, which did not increase after
nematode infection. Finally, we found that Rbbp9-deficient mice had a significantly diminished capacity to increase pulmonary
Il33 mRNA expression following
nematode infection. Thus, the
PGE2-EP2/EP4 pathway activated by RBBP9 released from damaged lungs is important for pulmonary
IL-33 production in nematode-infected animals.